E2 regulates MMP-13 via targeting miR-140 in IL-1β-induced extracellular matrix degradation in human chondrocytes

Abstract

BackgroundEstrogen deficiency is closely related to the development of menopausal arthritis. Estrogen replacement therapy (ERT) shows a protective effect against the osteoarthritis. However, the underlying mechanism of this protective effect is unknown. This study aimed to determine the role of miR-140 in the estrogen-dependent regulation of MMP-13 in human chondrocytes.MethodsPrimary human articular chondrocytes were obtained from female OA patients undergoing knee replacement surgery. Normal articular chondrocytes were isolated from the knee joints of female donors after trauma and treated with interleukin-1 beta (IL-1β). Gene expression levels of miR-140, MMP-13, and ADAMTS-5 were detected by quantitative real-time PCR (qRT-PCR). miR-140 levels were upregulated or downregulated by transfecting cells with a miRNA mimic and inhibitor, respectively, prior to treatment with IL-1β. MMP-13 expression was then evaluated by Western blotting and immunofluorescence. Luciferase reporter assays were performed to verify the interaction between miR-140 and ER.Results17-β-estradiol (E2) suppressed MMP-13 expression in human articular chondrocytes. miR-140 expression was upregulated after estrogen treatment. Knockdown of miR-140 expression abolished the inhibitory effect of estrogen on MMP-13. In addition, the estrogen/ER/miR-140 pathway showed an inhibitory effect on IL-1β-induced cartilage matrix degradation.ConclusionsThis study suggests that estrogen acts via ER and miR-140 to inhibit the catabolic activity of proteases within the chondrocyte extracellular matrix. These findings provide new insight into the mechanism of menopausal arthritis and indicate that the ER/miR-140 signaling pathway may be a potential target for therapeutic interventions for menopausal arthritis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-0997-y) contains supplementary material, which is available to authorized users.

MicroRNAs in orthopaedic research: Disease associations, potential therapeutic applications, and perspectives

“…74 Interestingly, when miR-140 was over-expressed in Col2a1-expressing cells, these mice appeared to be somewhat protected from proteoglycan and type II collagen loss following antigen-induced arthritis (AIA), an arthritic injury model that results in severe inflammation within the synovial joint. These findings, together with other reports that miR-140 has anti-catabolic or pro-anabolic effects in chondrocytes [74][75][76][77][78][79] suggests that targeting this miRNA could be a promising therapeutic approach to treat inflammation-induced cartilage degradation. Interestingly, a recent study showed that exosomes derived from rat synovial mesenchymal stem cells (SMSCs) and engineered to over-express miR-140 (SMSC-140-Exos) are chondroprotective.…”

Chondroprotective Effects of Ginsenoside Rg1 in Human Osteoarthritis Chondrocytes and a Rat Model of Anterior Cruciate Ligament Transection

“…In addition to bone-inducing effects, estrogen sustains normal chondrocyte metabolism and reduces the sensitization of articular cartilage to OA pathogenic factors [20]. Thus, we suggest that Rg1 may exert estrogen-like effects in OA treatment.…”

“…MMP-13 plays a pivotal role in initiating the degradation of type II collagen [20]. Previous studies have shown that herbs can decrease MMP-13 expression, when administered as complementary OA treatment [7,21].…”

Exosomes derived from miR-140-5p-overexpressing human synovial mesenchymal stem cells enhance cartilage tissue regeneration and prevent osteoarthritis of the knee in a rat model

“…Recently, miR-140-5p gained a lot of attention for playing dual roles in both cartilage homeostasis and development 36, 37 by targeting RalA to enhance SOX9 and aggrecan (ACAN) 38 and showing potential for preventing OA 39, 40.…”